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The self-association of amylogenic proteins to the fibril form is considered a pivotal factor in the pathogenesis of neurodegenerative diseases, including Parkinson’s disease (PD). PD causes unintended or uncontrollable movements in its common symptoms. α-synuclein is the major cause of PD development and thus has been the main target of numerous studies to suppress and sequester its expression or effectively degrade it. Nonetheless, to date, there are no efficient and proven ways to prevent pathological protein aggregation. Recent investigations proposed applying an external electric field to interrupt the fibrils. This method is a non-invasive approach that has a certain benefit over others. We performed molecular dynamics (MD) simulations by applying an electric field on highly toxic fibrils of α-synuclein to gain a molecular-level insight into fibril disruption mechanisms. The results revealed that the applied external electric field induces substantial changes in the conformation of the α-synuclein fibrils. Furthermore, we show the threshold value for electric field strength required to completely disrupt the α-synuclein fibrils by opening the hydrophobic core of the fibril. Thus, our findings might serve as a valuable foundation to better understand molecular-level mechanisms of the α-synuclein fibrils disaggregation process under an applied external electric field.

Transient receptor potential melastatin 8 (TRPM8), a cold-mediated ion channel, is well known to be expressed in primary sensory neurons; however, limited information is currently available on the distribution of TRPM8-expressing trigeminal nerve fibers in the brainstem. The present study showed the distribution of TRPM8-expressing fibers in the pons and medulla oblongata of the TRPM8 KO mice engineered by knocking in EGFP at the frame of the start codon of TRPM8. In addition, TRPM8-expressing fibers were also observed in the brachium pontis, middle cerebellar peduncle, the sensory root of the trigeminal nerve, and spinal trigeminal tract (sp5). Furthermore, TRPM8-expressing nerve fibers surrounded the somata of HuC/D-positive neurons in the sp5. Moreover, the distribution of TRPM8-expressing fibers from rostral to caudal was visualized in sagittal sections of the mouse brain. The present results also revealed that a high number of TRPM8-expressing fibers colocalized with CTB-labeled fibers in the sp5 following an injection of CTB into the whisker compared to mice's eye and ear. These results show the distribution pathway of TRPM8-expressing fibers in the pons and medulla oblongata and possible involvement in peripheral signaling from the trigeminal nerve.

Transient receptor potential melastatin 8 (TRPM8) functions in the sensing of noxious and innocuous colds; however, its significance in pathogen-induced thermoregulation remains unclear. In the present study, we investigated the role of TRPM8 in the regulation of endotoxin-induced body temperature control. The peripheral administration of low-dose lipopolysaccharide (LPS) at 50 ​μg/kg generated fever in wild-type (WT) mice, whereas it caused hypothermia in TRPM8 knockout (KO) animals. LPS-induced sickness responses such as decrease in body weight, and food and water intake were not different between WT and TRPM8 KO mice. TRPM8 KO mice exhibited more severe hypothermia and lower locomotor activity following the peripheral administration of high-dose LPS at 5 ​mg/kg compared with WT ones. An intracerebroventricular (i.c.v.) injection of either LPS at 3.6 ​μg/kg or interleukin-1β at 400 ​ng/kg elicited hypothermia in TRPM8 KO mice, in contrast to fever in WT animals. The peripheral administration of zymosan at 3 ​mg/kg also induced hypothermia in contrast to fever in WT mice. An i.c.v. injection of prostaglandin E2 at 16 or 160 ​nmol/kg induced normal fever in both WT and TRPM8 KO mice. Infrared thermography showed significant decline of the interscapular skin temperature that estimates temperature of the brown adipose tissue, regardless of no alteration of its temperature in WT animals. Fos immunohistochemistry showed stronger Fos activation of hypothalamic thermoregulation-associated nuclei in TRPM8 KO mice compared with WT animals following the peripheral administration of low-dose LPS. Therefore, the present study indicates that TRPM8 is necessary for switching between fever and hypothermia during endotoxin-induced inflammation., Graphical abstract Image 1, Highlights • Low-dose LPS (ip) caused hypothermia in TRPM8 KO animals versus fever in WT ones. • TRPM8 KO mice showed severe hypothermia by high-dose LPS (ip). • Central LPS injection elicited hypothermia in TRPM8 KO mice versus fever in WT ones. • Low-dose LPS (ip) caused decrease in BAT temperature. • Low-dose LPS (ip) caused more hypothalamic Fos expression in TRPM8 KO mice than WT.

Transient receptor potential melastatin 8 (TRPM8) functions in the sensing of noxious and innocuous colds; however, its significance in pathogen-induced thermoregulation and inflammation remains unclear. In the present study, we investigated the role of TRPM8 in the regulation of endotoxin-induced body temperature control and inflammation. The peripheral administration of low-dose LPS or zymosan generated fever in wild-type (WT) mice and hypothermia in TRPM8 knockout (KO) animals. TRPM8 KO mice exhibited severe hypothermia and sickness responses following the peripheral administration of high-dose LPS. An intracerebroventricular injection of LPS and interleukin-1ß (Il-1ß) elicited hypothermia in TRPM8 KO mice, in contrast to fever in WT animals, whereas that of prostaglandin E2 induced normal fever. Fos immunohistochemistry showed the stronger activation of hypothalamic thermoregulation-associated nuclei following the peripheral administration of low-dose LPS. Therefore, TRPM8 is necessary for switching between fever and hypothermia during endotoxin-induced inflammation.

Thermal homeostasis in mammalians is a self-regulating process by which biological systems maintain an internal thermal stability, even under different temperature conditions; however, the molecular mechanisms involved under warm ambient temperature remain unclear. Here, we aimed to clarify functional significance of transient receptor potential vanilloid receptor 1 (TRPV1) under warm ambient temperature. TRPV1 KO mice exhibited transient hyperthermia when exposed to 30.0 and 32.5 °C, whereas wild-type (WT) mice did not. TRPV1 KO mice exhibited prolonged and prominent hyperthermia upon exposure to 35.0 °C, whereas WT mice showed transient hyperthermia. Hyperthermia also occurs in WT mice that received intracerebroventricular injection of TRPV1 antagonist AMG9810 upon exposure to 35.0 °C. Heat loss behaviors, sleeping and body licking, were deficient in TRPV1 KO mice exposed to warm temperatures. Therefore, the present results indicate that central TRPV1 is crucial for maintaining a constant body temperature via the initiation of heat loss behaviors under warm ambient temperature.

Key points We found that extracellular Ca2+ , but not other divalent cations (Mg2+ and Ba2+ ) or intracellular Ca2+ , is involved in heat-evoked activation of green anole (ga) TRPA1. Heat-evoked activation of chicken (ch) and rat snake (rs) TRPA1 does not depend solely on extracellular Ca2+ . Neutralization of acidic amino acids on the outer surface of TRPA1 by extracellular Ca2+ is important for heat-evoked large activation of gaTRPA1, chTRPA1 and rsTRPA1. Abstract Transient receptor potential ankyrin 1 (TRPA1) is a homotetrameric non-selective cation-permeable channel that has six transmembrane domains and cytoplasmic N- and C-termini. The N-terminus is characterized by an unusually large number of ankyrin repeats. Although the 3-dimensional structure of human TRPA1 has been determined, and TRPA1 channels from insects to birds are known to be activated by heat stimulus, the mechanism for temperature-dependent TRPA1 activation is unclear. We previously reported that extracellular Ca2+ , but not intracellular Ca2+ , plays an important role in heat-evoked TRPA1 activation in green anole lizards (gaTRPA1). Here we focus on extracellular Ca2+ -dependent heat sensitivity of gaTRPA1 by comparing gaTRPA1 with heat-activated TRPA1 channels from rat snake (rsTRPA1) and chicken (chTRPA1). In the absence of extracellular Ca2+ , rsTRPA1 and chTRPA1 are activated by heat and generate small inward currents. A comparison of extracellular amino acids in TRPA1 identified three negatively charged amino acid residues (glutamate and aspartate) near the outer pore vestibule that are involved in heat-evoked TRPA1 activation in the presence of extracellular Ca2+ . These results suggest that neutralization of acidic amino acids by extracellular Ca2+ is important for heat-evoked activation of gaTRPA1, chTRPA1, and rsTRPA1, which could clarify mechanisms of heat-evoked channel activation.

Tanycyte is a subtype of ependymal cells which extend long radial processes to brain parenchyma. The present study showed that tanycyte-like ependymal cells in the organum vasculosum of the lamina terminalis, subfornical organ and central canal (CC) expressed neural stem cell (NSC) marker nestin, glial fibrillar acidic protein and sex determining region Y. Proliferation of these tanycyte-like ependymal cells was promoted by continuous intracerebroventricular infusion of fibroblast growth factor-2 and epidermal growth factor. Tanycytes-like ependymal cells in the CC are able to form self-renewing neurospheres and give rise mostly to new astrocytes and oligodendrocytes. Collagenase-induced small medullary hemorrhage increased proliferation of tanycyte-like ependymal cells in the CC. These results demonstrate that these tanycyte-like ependymal cells of the adult mouse brain are NSCs and suggest that they serve as a source for providing new neuronal lineage cells upon brain damage in the medulla oblongata.

The choroid plexus (CP), located at the walls of the brain ventricles, produces and secretes cerebrospinal fluid (CSF). Hydrocephalus is a neurological disorder in which the CP abnormally secretes excess amounts of CSF into the ventricles. There is currently no information on the vascular dynamics of the CP in adult brains under normal and hydrocephalic conditions. In the present study, we reported the continuous proliferation of endothelial cells in the CP of normal mice, which depended on vascular endothelial cell growth factor (VEGF). The proliferation of endothelial cells increased in mice with intraventricular hemorrhage, which was attenuated by a pretreatment with the toll-like receptor 4 (TLR4) inhibitor VIPER. Moreover, the intracerebroventricular infusion of the TLR4 agonist, lipopolysaccharide, increased endothelial cell proliferation in the CP and induced ventriculomegaly. The present results provide insights into the importance of the TLR4-initiated and VEGF-dependent proliferation of endothelial cells in the pathogenesis of hydrocephalus.

Transient receptor potential, ankyrin 1 (TRPA1) is a homotetrameric nonselective cation- permeable channel with six transmembrane domains handed by cytoplasmic N and C termini. Although many TRP channel family members contain the range of 3-6 ankyrin repeats (AR) within the N-terminal region, TRPA1 is distinguished by having an unusually large number of such repeats (16-17 ARs). A number of studies have shown that both intracellular and extracellular Ca2+ is a key regulator of many TRP channels, including TRPA1. In the previous study, we found that extracellular Ca2+, but not intracellular Ca2+ plays an important role in heat-evoked activation of green anole TRPA1 (gaTRPA1). In this study, we focus on extracellular Ca2+-dependent heat sensitivity of gaTRPA1 by comparing gaTRPA1 with other heat-activated TRPA1s from rat-snake (rsTRPA1) and chicken (chTRPA1). We found that rsTRPA1 and chTRPA1s are activated by heat with small inward currents in the absence of extracellular Ca2+. We identified several negatively charged amino acid residues (glutamate and aspartate) near outer pore vestibule in gaTRPA1, chTRPA1 and rsTRPA1 for activation by heat in the presence of extracellular Ca2+. These results suggest that the neutralization of the acidic amino acids by extracellular Ca2+ is important for the heat-evoked activation of gaTRPA1, chTRPA1 and rsTRPA1.